The overall theme of this Program Project is to understand the mechanisms which regulate peripheral tolerance and to facilitate the implementation of scientific advances gained using in vitro model systems to the establishment of peripheral tolerance in vivo. Initiation and maintenance of peripheral T cell tolerance relies on a complex set of events dependent on the responding T cell subpopulation, the antigen and the antigen-presenting cells (APC), expression of co- stimulatory molecules and cytokines, and the genes expressed during the early signalling cascade following exposure to antigen. The overall goals are to dissect the mechanisms which lead to peripheral T cell tolerance by examining the molecular, biochemical, and immunobiological consequences of T cell interactions with antigen presenting cells. To achieve these general goals, three complementary projects will be undertaken: 1. To understand the interactions between receptor-mediated signal transduction pathways that regulate the functions of different T lymphocyte subsets. The Pis will further characterize the signaling block in anergic T cells to produce IL-2. They also will characterize the CD28-mediated signaling events that promote augmented cytokine gene expression and that prevent energy induction, focussing on serine/threonine kinase intermediates that may lead to activation of Jnk-1/Jnk-2. They will identify additional costimulatory molecules that regulate the growth of Th2 cells. 2. To define the molecular basis of for the activity of co-stimulatory molecules. The PI will continue to define the molecular basis of the opposing effects of CTLA-4 and CD28 on the immune response in collaboration with the other Program Project investigators. In addition, Dr. Thompson will study the role CD30, 4-1-BB, and OX40 as co-stimulatory molecules, emphasizing the role of the TRAF family of molecules in mediating their effects. He also will continue his studies of the role of co-stimulation in preventing apoptosis through the bcl-xl and Fas pathways. 3. To determine the mechanisms of tolerance induction and the individual roles of CD28/CTLA-4 and B7- 1/B7-2. The PI will determine the individual roles of B7-1 and B7-2 on donor and host tissues during the initiation and progression of transplant rejection. He also will further characterize the biological effects of CTLA4 engagement and blockade on exposure to antigen in vitro and in vivo, determining the importance of the stage of the immune response, the tissue transplanted, and the APC targeted. These projects should provide information on the mechanism of peripheral T cell tolerance and help develop new therapeutic approaches for autoimmunity and graft rejection.